Abstract
Y-box binding protein 1 (YB-1) is a well-known oncogene highly expressed in various cancers, including basal-like breast cancer (BLBC). Beyond its role as a transcription factor, YB-1 is newly defined as an epigenetic regulator involving RNA 5-methylcytosine. However, its specific targets and pro-cancer functions are poorly defined. Here, based on clinical database, we demonstrate a positive correlation between Kruppel-like factor 5 (KLF5) and YB-1 expression in breast cancer patients, but a negative correlation with that of Dachshund homolog 1 (DACH1). Mechanistically, YB-1 enhances KLF5 expression not only through transcriptional activation that can be inhibited by DACH1, but also by stabilizing KLF5 mRNA in a RNA 5-methylcytosine modification-dependent manner. Additionally, ribosomal S6 kinase 2 (RSK2) mediated YB-1 phosphorylation at Ser102 promotes YB-1/KLF5 transcriptional complex formation, which co-regulates the expression of BLBC specific genes, Keratin 16 (KRT16) and lymphocyte antigen 6 family member D (Ly6D), to promote cancer cell proliferation. The RSK inhibitor, LJH685, suppressed BLBC cell tumourigenesis in vivo by disturbing YB-1-KLF5 axis. Our data suggest that YB-1 positively regulates KLF5 at multiple levels to promote BLBC progression. The novel RSK2-YB-1-KLF5-KRT16/Ly6D axis provides candidate diagnostic markers and therapeutic targets for BLBC.
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Data availability
High throughput sequencing data are available at https://doi.org/10.6084/m9.figshare.13605839.v1 and https://doi.org/10.6084/m9.figshare.13605833.v1. Original IHC images are available at https://doi.org/10.6084/m9.figshare.16621180.v1. Other datasets and materials are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank Prof. Yun-Gui Yang (Beijing Institute of Genomics, Chinese Academy of Sciences) for kindly offering pCMV-NSUN2 wt/c321a constructs.
Funding
This work was supported by National Key R&D Program of China (2020YFA0112300 and 2020YFA0803200), National Science Foundation of China (81672639 to ZZ; 81830087, U2102203 and 31771516 to CC; 81802671, 81872414 and 82173014 to DJ; 81972791 to XM), CAS “Light of West China” Young Scholar Program to DJ, Yunnan Fundamental Research Projects (202001AW070018, 202101AS070050, and 2019FB112), and Project of Innovative Research Team of Yunnan Province (2019HC005)
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CC, MZ, XM and DJ designed and supervised the study. DJ, TQ, JP, and SL performed most of the experiments and analyses. WR, JS, CHC, YW and Tala participated in some experiments. CY and YW performed and analyzed clinical and experimental IHC data. WL, RL, JZ and KW participated in discussion. DJ, CC, and TQ draft the manuscript. All authors discussed and finalized this paper.
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Jiang, D., Qiu, T., Peng, J. et al. YB-1 is a positive regulator of KLF5 transcription factor in basal-like breast cancer. Cell Death Differ 29, 1283–1295 (2022). https://doi.org/10.1038/s41418-021-00920-x
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DOI: https://doi.org/10.1038/s41418-021-00920-x
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